Qualitative assessment of healthy volunteer experience receiving subcutaneous infusions of high-dose benzathine penicillin G (SCIP) provides insights into design of late phase clinical studies

Abstract

Introduction Secondary prophylaxis to prevent rheumatic heart disease (RHD) progression, in the form of four-weekly intramuscular benzathine benzylpenicillin G (BPG) injections, has remained unchanged since 1955. Qualitative investigations into patient preference have highlighted the need for long-acting penicillins to be delivered less frequently, ideally with reduced pain. We describe the experience of healthy volunteers participating in a phase-I safety, tolerability and pharmacokinetic trial of subcutaneous infusions of high-dose benzathine penicillin G (BPG)–the SCIP study (Australian New Zealand Clinical Trials Registry ACTRN12622000916741). Methods Participants (n = 24) received between 6.9 mL to 20.7 mL (3–9 times the standard dose) of BPG as a single infusion into the abdominal subcutaneous tissues via a spring-driven syringe pump over approximately 20 minutes. Semi-structured interviews at four time points were recorded, transcribed verbatim and thematically analysed. Tolerability and specific descriptors of the experience were explored, alongside thoughts on how the intervention could be improved for future trials in children and young adults receiving monthly BPG intramuscular injections for RHD. Results Participants tolerated the infusion well and were able describe their experiences throughout. Most reported minimal pain, substantiated via quantitative pain scores. Abdominal bruising at the infusion site did not concern participants nor impair normal activities. Insight into how SCIP could be improved for children included the use of topical analgesia, distractions via television or personal devices, a drawn-out infusion time with reduced delivery speed, and alternative infusion sites. Trust in the trial team was high. Conclusion Qualitative research is an important adjunct for early-phase clinical trials, particularly when adherence to the planned intervention is a key driver of success. These results will inform later-phase SCIP trials in people living with RHD and other indications.

“Hurts less, lasts longer”; a qualitative study on experiences of young people receiving high-dose subcutaneous injections of benzathine penicillin G to prevent rheumatic heart disease in New Zealand

“…Administering BPG through a series of slow pushes enabled greater control in the rate of delivery in comparison to the spring infuser used in the Phase-I trial. This potentially led to slightly shorter injection times; Phase-I mean time of 22 minutes, range 16–29 minutes [ 21 ], compared to a mean of 15 minutes, range of 9–25 minutes, in Phase-II. In addition, participants in the Phase-II trial reported slightly lower pain scores during the injection in comparison to the Phase-I trial (median NRS 1.0, range 0–7 median compared to median NRS 2.5, range 0–8) [ 20 ].…”

“…The study concluded that delivering high-dose BPG by SC infusion was safe, had acceptable tolerability and could be suitable for up to three-monthly dosing intervals for secondary prophylaxis of ARF/RHD [ 20 ]. In addition to the Phase-I trial, a qualitative sub-study was undertaken to provide in-depth information about the tolerability and acceptability of the delivery method [ 21 ]. The sub-study demonstrated that the procedure was acceptable to participants, and while some experienced high pain levels, most had tolerable mild discomfort.…”

“Hurts less, lasts longer” experiences of young people receiving high-dose subcutaneous infusions of benzathine penicillin G to prevent rheumatic heart disease

“…By delivering BPG through a series of slow pushes there was a greater control, in comparison to the spring infuser used in SCIP-I, over the rate the BPG was delivered. This potentially led to slightly shorter infusion times; SCIP-I - mean infusion time of 22 minutes, range 16-29 minutes [20], compared to a mean of 15 minutes, range of 9-25 minutes, in SCIP-II. In addition, participants in SCIP-II reported slightly lower pain scores during the infusion in comparison to SCIP-I (median NRS 1.0, range 0-7 median compared to median NRS 2.5, range 0-8) [19].…”

“…The study concluded that delivering high-dose SCIP was safe, had acceptable tolerability and could be suitable for up to three-monthly dosing intervals for secondary prophylaxis of ARF/RHD [19]. In addition to the Phase-I trial, a qualitative sub-study was undertaken to provide in-depth information about the tolerability and acceptability of SCIP [20]. The sub-study demonstrated that SCIP was acceptable to participants, and while some experienced higher pain levels, most had tolerable mild discomfort.…”

Subcutaneous infusion of high-dose benzathine penicillin G is safe, tolerable, and suitable for less-frequent dosing for rheumatic heart disease secondary prophylaxis: a phase 1 open-label population pharmacokinetic study

“…Interviews were recorded, transcribed verbatim, and analyzed using thematic analysis. The qualitative assessment of the volunteer experience of SCIP has been reported separately ( 32 ).…”